Every year more than 210,000 women in the United States develop breast cancer. One in eight women in the US will develop breast cancer during their lives. Approximately 70 percent of breast cancers are fueled by estrogen, and many are treated with Tamoxifen, a drug designed to block the effects of estrogen in breast tissue.
Tamoxifen is an anti-estrogenic drug prescribed for long-term, low dose therapy of breast cancer. It has been widely used for more than 30 years for the endocrine treatment of all stages of hormone receptor-positive breast cancer (1-2). Tamoxifen has also been approved for the prevention of breast cancer (3). In women, one of the adverse events associated with Tamoxifen is hot flashes. The risk of hot flashes is two to three-folds higher among women who take Tamoxifen than it is for those who do not (4). Selective serotonin-reuptake inhibitor (SSRI) antidepressants are prescribed to treat hot flashes. However, some SSRIs, such as paroxetine and fluoxetine, are known to inhibit cytochrome P450 (CYP) 2D6 (5), an enzyme that is important for the metabolism of many drugs, including Tamoxifen. Our understanding of Tamoxifen metabolism and effect has changed clinical practice through the wide spread recognition that the co-prescription of drugs that inhibit CYP2D6 may compromise Tamoxifen efficacy. It is known that co-administration of paroxetine decreases the plasma concentration of an active metabolite of Tamoxifen, 4-hydroxy-N-desmethyl-Tamoxifen (endoxifen).
Endoxifen is generated via CYP3A4-mediated N-demethylation and CYP2D6 mediated hydroxylation of Tamoxifen (see, e.g., FIG. 3). Any drug that can be substrate of CYP3A4 or CYP2D6, especially CYP2D6 e.g., SSRIs, can decrease the level of endoxifen (6) and thus reduce the therapeutic benefits of Tamoxifen. Therefore, to avoid such drug-drug interactions, one should not give them together.
Recently, endoxifen has been shown to be anti-estrogenic in breast cancer cells and to be more potent than Tamoxifen (7). In patients treated with Tamoxifen, endoxifen is present in higher concentration (12.4 ng/mL) than 4-OH-tamoxifen (1 ng/mL) in the human plasma. The majority of genes affected by endoxifen are estrogen-regulated genes (8-9). Use of endoxifen e.g., in place of Tamoxifen, avoids several metabolic steps that rely on CYP2D6.
A strong need exists for methods to treat and to prevent breast diseases without significant adverse systemic side effects, particularly in the premenoposal population. In particular, there is a need for breast cancer treatments and preventatives that having reduced interactive effect with other medications.